. Lower motor neuron involvement in TAR DNA-binding protein of 43 kDa-related frontotemporal lobar degeneration and amyotrophic lateral sclerosis. JAMA Neurol. 2014 Feb;71(2):172-9. PubMed.

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  1. While many investigators have examined brain and spinal cord tissue with TDP in cases and small series, this is one of the largest systematic studies of TDP staining in brain and spinal-cord tissue among sporadic FTLD-ALS spectrum patients regardless of antemortem clinical syndrome (FTLD without ALS, FTLD-ALS, or ALS-FTLD). As would likely be expected by many investigators in this field, TDP pathology was evident across the upper- and lower-motor-neuron networks regardless of antemortem syndrome.

    These findings further support the view that the clinical and neuropathologic features of FTLD-ALS represents a spectrum with a likely similar pathophysiology, but the precise mechanisms involved in TDP-associated neurodegeneration remains unclear.

    TDP-43 ties together some of the genetically mediated FTLD and/or ALS disorders (e.g., progranulin, C9ORF72, and many others) as well as many sporadic FTD and/or ALS cases, but the whys and hows are not adequately understood.

    In my mind, these findings also underscore several important concepts relating to clinicopathologic correlations, more specifically: 1) antemortem detection of clinical deficits, 2) thresholds of clinical expression of neurodegeneration, and 3) protein deposition-neurodegeneration correlations. These concepts help to cloud the interpretation (but do not detract from the importance and significance) of any clinicopathologic study in neurodegenerative disease.

    1) Antemortem detection of clinical deficits: As patients evolve into the terminal phase of FTLD-ALS, they are typically not evaluated as frequently and perhaps also not as diligently, and therefore a patient with behavioral variant FTD (bvFTD) may develop ALS late in the course, or an ALS patient may develop bvFTD features late in life, and these may go undetected. If one assesses for bvFTD features in those with ALS, the features are often present even if they are not obvious or problematic (as demonstrated by Catherine Lomen-Hoerth and colleagues, and others). Furthermore, examining for bvFTD features becomes increasingly more difficult in progressively severe ALS patients, and vice versa. Finally, electromyography (EMG) may reveal electrophysiologic changes of lower-motor-neuron dysfunction that are not apparent on purely clinical grounds (this was also demonstrated by Lomen-Hoerth et al., and many others). Thus, some patients diagnosed with bvFTD may have ALS during life but not appreciated (and thus their final clinical diagnosis is bvFTD), and vice versa (and thus their final clinical diagnosis is ALS), thereby potentially altering the interpretation of clinicopathologic correlations in this paper and many other papers in neurodegenerative diseases.

    2) The thresholds of clinical expression of neurodegeneration: What degree of neuronal degeneration in frontotemporal neural networks is required to manifest as bvFTD? What degree of degeneration in upper motor neurons is required to manifest as the upper-motor-neuron dysfunction component of ALS? And what degree of degeneration in the lower motor neurons in cranial nuclei and spinal cord is necessary to manifest as the lower-motor-neuron dysfunction component of ALS? Is there patient-to-patient variability? Probably. These questions are not adequately answered, limiting the interpretation of clinical expression of neurodegeneration.

    3) Protein deposition-neurodegeneration correlations: Clinical deficits correlate with the corresponding neuronal dysfunction, but not necessarily with abnormal protein deposition in neurons and/or glia. In other words, the presence of TDP43 in any neuron may or may not be associated with functional impairment of that neuron; this same concept applies to the presence of other presumably abnormal protein accumulations (e.g., α-synuclein) in neurons. Therefore, finding TDP deposition in lower motor neurons in a patient with bvFTD throughout life may suggest a continuum of TDP deposition along the motor-neuron axis, but whether that patient ever would have exhibited ALS features had he/she lived long enough is not known.

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